The three human salivary cystatins S, SA and SN are multifunctional proteins and in common with other cystatin proteins they possess a cysteine protease inhibitory property. This suggests they may play a role in the control of protein degradation within the oral environment. Proteolytic events resulting in the destruction of oral tissues are associated with periodontal diseases. This tissue destruction can be attributed in part to the release of proteolytic enzymes by colonizing bacteria. The subsequent biochemical events can lead to the activation of host proteolytic enzymes and the release of host cysteine proteases, such as the cathepsins B, H and L, which in turn lead to further tissue degradation. Our data indicates that the human salivary cystatins are able to inhibit these cathepsins in vitro, as well as the cysteine proteases papain and cruzain. Although these cystatins (S, SA and SN) are 90% homologous, they vary greatly in their inhibition properties towards these cysteine proteases. Models of the three salivary cystatins suggest that the inhibitory loop domain of the three salivary cystatins showed only slight variation in structure. The aim of our current study is to model the interactions of each of the salivary cystatins and chicken cystatin with the cysteine proteases papain, cruzain and cathepsin B to explain the major differences we have found in the ability of S, SA and SN to inhibit the activity of these proteases. Identification of critical residues involved in binding of these inhibitors to the above named proteases will allow us to search for homologous sequences in identified cysteine proteases that may be present in the oral environment, and better understand the roles of the salivary cystatins in disease prevention. Identification of the cysteine protease targets for the human salivary cystatins in the oral environment will contribute to the understanding of the complex mechanisms involved in tissue destructive diseases such as periodontal diseases. This work will potentially result in the design of measures for risk assessment and/or prevention of such diseases.